Venous Thrombo-Embolism (VTE) Therapy current challenges & opportunities

Venous Thrombo-Embolism (VTE) Therapy current challenges & opportunities Asher Winder M.D. Director, Department of Hematology Wolfson Medical Center כנס האיגוד הישראלי לפרמקולוגיה קלינית 2012 04-May-2012

Venous Thrombo-Embolism (VTE) A pulmonary embolism (PE) is the consequence of mobilization of a deep vein thrombosis (DVT) PE and DVT are therefore considered to be two clinical manifestations of the same disease

VTE Therapy Anticoagulation What is the optimal duration of oral anticoagulant therapy after an episode of VTE? Provoked VTE 3-6 months Unprovoked VTE 6-12 months Recurrent VTE life long treatment prevention Modified from Kearon C et al. Chest 2012;141:e419S-e494S

Fibrinolysis Clot lysis and vessel repair begins immediately after the formation of the definitive hemostatic plug. Tissue plasminogen activator (tpa) and urokinase (upa), diffuse from endothelial cells and convert plasminogen, adsorbed to the fibrin clot, into plasmin. Plasmin then degrades fibrin polymer into small fragments. tpa and upa are regulated by plasminogen activator inhibitor-1 (PAI-1); plasmin is regulated by a2-plasmin inhibitor (a2-pi).

The objective of treating venous thrombosis --to prevent local extension of the thrombus, --to prevent the thrombus from embolizing -- to avoid the chronic complications --to induce accelerated fibrinolysis. How long does this take? and then to stop anticoagulation? 1. Kearon C. Circulation 2003;107:I22 I30; 2. Ginsberg JS, et al. Arch Intern Med 2000;160:669 672

Recurrence Rate in 929 Patients With A First Unprovoked VTE 95% CIs (dotted lines) Eichinger S, et al. Circulation. 2010;121:1630-1636.

Recurrent VTE is Common after A First Episode of Symptomatic DVT Idiopathic vs Secondary VTE A prospective cohort study in 1626 patients Adjusted HR = 2.30 (95% CI, 1.82-2.90) P. Prandoni et al. Haematologica. 2007 Feb;92(2):199-205.

Risk of recurrent VTE after stopping anticoagulant therapy provocation after 1 year % after 5 years % surgery 1 3 nonsurgical reversible risk factor * 5 15 Unprovoked 10 30 Cancer ** 15 * nonsurgical trigger : eg, estrogen therapy, pregnancy, leg injury, flight of > 8 h ** cancer: vary according to whether the cancer is metastatic, being treated with chemotherapy, or rapidly progressing) CHEST February 2012 vol. 141 no. 2 suppl e419s-e494s

Recurrence (%) Duration of Anticoagulation for First Unprovoked DVT 30 20 3 months (INR 2-3) 12 months (INR 2-3) 10 Indefinite (INR 1.5-2) Indefinite (INR 2-3) 1 2 3 Years

treatment duration does not seem to influence recurrent VTE risk in patients with unprovoked VTE; longer anticoagulation seems to simply delay recurrence Conclusion: give anticoagulants life time? Bleeding Thrombosis Coagulation

Annual major hemorrhage rates in recent trials of long-term full-intensity and longterm low-intensity warfarin therapy in the prevention of recurrent VTE Ridker P.M. J Thrombos Haemos 2004;2(7):1034

Thromboembolism and Hemorrhage by Age Adjusted HR 3 2.5 2 1.5 1 0.5 0 Age groups <60 60-70 71-80 >80 T-E Hemorrhage Leiden Clinic, 1994-1998. N = 4202 Torn M et al. Arch Intern Med 2005;165:1527-32

Time period of treatment Provoked VTE 3-6 months Unprovoked VTE 6-12 months Recurrent VTE life long What strategies for optimal duration of oral anticoagulant therapy after an episode of VTE?

Do positive thrombophilia tests predict increased risk of recurrent VTE? Factor V Leiden (+/-) Prothrombin 20210 (+/-) APLA (LAC) AT, PC,PS, multiple risks NO NO YES excluded/too rare

Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation Cumulative incidence of recurrent thromboembolism OAT = oral anticoagulant therapy flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in patients with recanalized veins and continued anticoagulation in all other patients for up to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis) Prandoni P. et al. Ann Intern Med 2009;150:577-585

Hazard for recurrent VTE by D-dimer status timing of D-dimer testing D-dimer status in patient subgroups defined by age. Douketis A. et al. Ann Intern Med. 2010;153:523-531.

Risk Assessment of Recurrence in Patients With Unprovoked VTE The Vienna Prediction Model Eichinger S, et al. Circulation. 2010;121:1630-1636.

In patients with a first VTE that is an unprovoked VTE bleeding risk duration grade proximal DVT low or moderate PE extended 2B high 3 months 1B low or moderate extended 2B high 3 months 1B CHEST 2012; 141(2)(Suppl)

Phases of anticoagulation. We use the term extended anticoagulation to refer to anticoagulation that is continued beyond 3 months without a scheduled stop date. However, regular (eg, yearly) reassessments are needed to assess whether a patient s risk of bleeding increased or the patient s preferences changed. Kearon C et al. Chest 2012;141:e419S-e494S

If we only had an anticoagulant agent effective as warfarin but with less risk for bleeding! One more thing, we are tired of injections and tired of the need for switching to oral agent!

The (Good) Old Days Aspirin Heparin Warfarin (Coumadin)

Aspirin for Preventing the Recurrence of Venous Thromboembolism (WARFASA ) Becattini C, et al. N Engl J Med 2012; 366:1959-1967 May 24, 2012

Antithrombotic Therapy 2012 Approved by Israeli MoH Antiplatalet Aspirin ADP receptor inhibitors - Thienopyridines Ticlopidine Clopidrogel Prasugrel (Effient) Ticagrelor (Brilinta) Dipyridamol (Aggrenox) GPIIb-IIIa inhibitors Abciximab (ReoPro) Tirofiban (Aggrastat) Eptifibatide (Integrilin) Anticoagulants Heparins UFH LMWH Danaparoid Coumadin, Sintrom Bivalirudin (Angiomax) Fondaparinux (Arixtra) (Xarelto) Dabigatran (Pradaxa) Fibrinolytics SK U-PA rt-pa

New anticoagulants ORAL PARENTERAL TTP889 TF/VIIa TFPI (tifacogin) X IX Apixaban LY517717 YM150 DU-176b PRT-054021 Ximelagatran Dabigatran IXa VIIIa Va Xa II IIa AT APC (drotrecogin alfa) stm (ART-123) Fondaparinux Idraparinux DX-9065a Otamixaban Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

Direct Factor Xa inhibition XIIa Tissue factor XIa IXa Xa Factor II (prothrombin) VIIa Apixaban DU-176b YM150 LY517717 PRT-054021 Fibrinogen Fibrin clot

O O N N O N H S Cl Direct Factor Xa Inhibitors S4 O O S1 FXa Human Factor Xa/rivaroxaban complex Direct FXa inhibitors FXa in the prothrombinase complex Direct Factor Xa inhibitors can inhibit Factor Xa within the prothrombinase complex Roehrig et al., J Med Chem 2005; Perzborn et al., J Thromb Haemost 2005

Direct, specific, competitive Factor Xa inhibitor High oral bioavailability Rapid onset of action Half-life: 7 11 hours Dual mode of elimination: 1/3 of drug excreted unchanged by the kidneys 2/3 of drug metabolized by the liver: half excreted renally; half excreted by the fecal route No dietary restrictions O N N O N H O O O S Cl

clinical programme clinical trial programme of >75,000 patients in 5 indications ` Phase II Phase III VTE prevention after elective hip or knee replacement surgery VTE prevention in hospitalized medically ill patients ODIXa-HIP1 ODIXa-HIP2 ODIXa-KNEE ODIXa-OD.HIP RECORD1 RECORD2 RECORD3 RECORD4 VTE treatment Stroke prevention in atrial fibrillation ODIXa-DVT EINSTEIN-DVT EINSTEIN DVT EINSTEIN PE EINSTEIN EXT Secondary prevention of acute coronary syndromes

30-day observation after treatment cessation 30-day observation after treatment cessation EINSTEIN phase III: study designs Confirmed acute symptomatic DVT without symptomatic PE Confirmed acute symptomatic PE with or without symptomatic DVT N=3449 R N=4833 EINSTEIN DVT and EINSTEIN PE (non-inferiority studies) Treatment period of 3, 6 or 12 months 15 mg bid Enoxaparin 1.0 mg/kg bid for at least 5 days, followed by VKA to start 48 hours, target INR range 2.0 3.0 Day 1 Day 21 20 mg od Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA N=1197 R Day 1 EINSTEIN Extension (superiority study) Treatment period of 6 or 12 months 20 mg od Placebo 1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510; 2. The EINSTEIN PE Investigators. N Engl J Med 2012; 366:1287-1297

Cumulative event rate (%) EINSTEIN DVT: primary efficacy outcome time to first event 4.0 3.0 2.0 Enoxaparin/VKA (N=1718) (N=1731) 1.0 HR=0.68; p<0.001 (non-inferiority) RR=32% 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of subjects at risk 1731 1668 1648 1621 1424 1412 1220 400 369 363 345 309 266 Enoxaparin/ VKA 1718 1616 1581 1553 1368 1358 1186 380 362 337 325 297 264 RR, relative risk The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

EINSTEIN DVT: primary efficacy outcome analysis (N=1731) Enoxaparin/VKA (N=1718) n (%) n (%) First symptomatic recurrent VTE 36 (2.1) 51 (3.0) Recurrent DVT 14 (0.8) 28 (1.6) Recurrent DVT + PE 1 (<0.1) 0 (0.0) Non-fatal PE 20 (1.2) 18 (1.0) Fatal PE/unexplained death where PE cannot be ruled out 4 (0.2) 6 (0.3) 0 superior 0.44 0.68 1.04 HR p=0.08 for superiority (two-sided) CI, confidence interval; HR, hazard ratio ITT population 1.00 non-inferior p<0.001 for non-inferiority (one-sided) 2.00 inferior The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

EINSTEIN DVT: primary efficacy outcome by subgroup Symptomatic recurrent VTE Enoxaparin/VKA HR (95% CI) n/n (%) n/n (%) Overall 36/1731 (2.1) 51/1718 (3.0) Intended duration of anticoagulation 3 months 5/208 (2.4) 3/203 (1.5) 6 months 25/1083 (2.3) 29/1083 (2.7) 12 months 6/440 (1.4) 19/432 (4.4) VKA received Warfarin 28/1249 (2.2) 41/1256 (3.3) Acenocoumarol 7/377 (1.9) 9/380 (2.4) Prerandomization LMWH No 9/467 (1.9) 10/505 (2.0) Yes 27/1264 (2.1) 41/1213 (3.4) 0.1 1 10 Favours rivaroxaban Favours enoxaparin/vka ITT population The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510 (Supplementary Appendix)

Cumulative event rate (%) EINSTEIN DVT: principal safety outcome (composite of major or non-major clinically relevant bleeding) 14 12 10 8 6 Enoxaparin/VKA (N=1711) (N=1718) Number of subjects at risk 1718 1585 1538 1382 1317 1297 715 355 338 304 278 265 140 Enoxaparin/ VKA 4 2 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) 1711 1554 1503 1340 1263 1238 619 338 321 287 268 249 118 The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

EINSTEIN DVT: principal safety outcome analysis (N=1718) Enoxaparin/VKA (N=1711) HR (95% CI) n (%) n (%) p-value First major or non-major clinically relevant bleeding 139 (8.1) 138 (8.1) 0.97 (0.76 1.22) p=0.77 Major bleeding 14 (0.8) 20 (1.2) 0.65 (0.33 1.30) p=0.21 Contributing to death 1 (<0.1) 5 (0.3) In a critical site 3 (0.2) 3 (0.2) Associated with fall in haemoglobin 2 g/dl and/or transfusion of 2 units 10 (0.6) 12 (0.7) Non-major clinically relevant bleeding 126 (7.3) 119 (7.0) Patients could have one or more bleeding events Safety population The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

EINSTEIN PE: study design Randomized, open-label, event-driven, non-inferiority study Up to 48 hours heparins/fondaparinux treatment permitted before study entry 88 primary efficacy outcomes needed Non-inferiority margin: 2.0 Predefined treatment period of 3, 6 or 12 months Day 1 Day 21 Objectively confirmed PE ± DVT N=4833 R 15 mg bid 20 mg od Enoxaparin (1 mg/kg) bid for at least 5 days, plus VKA target INR 2.5 (INR range 2.0 3.0) 30-day observation period after treatment cessation The EINSTEIN PE Investigators. N Engl J Med 2012; 366:1287-1297

Cumulative event rate (%) Primary efficacy outcome: time to first event 3.0 2.5 N=2419 2.0 1.5 1.0 0.5 Enoxaparin/VKA N=2413 HR=1.12; p<0.0026 (non-inferiority) 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of patients at risk 2419 2350 2321 2303 2180 2167 2063 837 794 785 757 725 672 Enoxaparin/VKA 2413 2316 2296 2274 2157 2149 2053 837 789 774 748 724 677 ITT population The EINSTEIN PE Investigators. N Engl J Med 2012; 366:1287-1297

Primary efficacy outcome analysis (N=2419) Enoxaparin/VKA (N=2413) n (%) n (%) First symptomatic recurrent VTE 50 (2.1) 44 (1.8) Recurrent DVT 18 (0.7) 17 (0.7) Recurrent DVT + PE 0 2 (<0.1) Non-fatal PE 22 (0.9) 19 (0.8) Fatal PE/unexplained death where PE cannot be ruled out 10 (0.4) 6 (0.2) superior ITT population p=0.57 for superiority (two-sided) 0.75 1.12 1.69 0 1.00 2.00 non-inferior p<0.0026 for non-inferiority (one-sided) inferior The EINSTEIN PE Investigators. N Engl J Med 2012; 366:1287-1297

Cumulative event rate (%) Principal safety outcome: major or non-major clinically relevant bleeding 15 14 13 12 11 10 9 8 7 N=2412 6 5 4 3 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Enoxaparin/VKA N=2405 Number of patients at risk 2412 2183 2133 2024 1953 1913 1211 696 671 632 600 588 313 Enoxaparin/VKA 2405 2184 2115 1990 1923 1887 1092 687 660 620 589 574 251 Safety population The EINSTEIN PE Investigators. N Engl J Med 2012; 366:1287-1297

Cumulative event rate (%) Major bleeding 3.0 2.5 2.0 Enoxaparin/VKA N=2405 1.5 1.0 0.5 N=2412 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of patients at risk 2412 2281 2248 2156 2091 2063 1317 761 735 700 669 659 350 Enoxaparin/VKA 2405 2270 2224 2116 2063 2036 1176 746 719 680 658 642 278 Safety population

Principal safety outcome analysis: major or non-major clinically relevant bleeding First major or non-major clinically relevant bleeding event (N=2412) Enoxaparin/VKA (N=2405) n (%) n (%) 249 (10.3) 274 (11.4) Major bleeding 26 (1.1) 52 (2.2) Contributing to death 2 (<0.1) 3 (0.1) HR (95% CI) p-value 0.90 (0.76 1.07) p=0.23 0.49 (0.31 0.80) p=0.0032 In a critical site 6 (0.2) 27 (1.1) Associated with fall in haemoglobin 2 g/dl and/or transfusion of 2 units Non-major clinically relevant bleeding 18 (0.7) 26 (1.1) 228 (9.5) 235 (9.8) Safety population The EINSTEIN PE Investigators. N Engl J Med 2012; 366:1287-1297

Major bleeding (N=2412) Enoxaparin/VKA (N=2405) n (%) n (%) Major bleeding* 26 (1.1) 52 (2.2) Fatal 2 (<0.1) 3 (0.1) Retroperitoneal 0 1 (<0.1) Intracranial 2 (<0.1) 2 (<0.1) In a critical site 6 (0.2) 26 (1.1) Intracranial 1 (<0.1) 10 (0.4) Retroperitoneal 1 (<0.1) 7 (0.3) Intraocular 2 (<0.1) 2 (<0.1) Pericardial 0 2 (<0.1) Intra-articular 0 3 (0.1) Adrenal gland 1 (<0.1) 0 Rectal/pulmonary/abdominal 1 (<0.1) 2 (<0.1) Fall in haemoglobin 2 g/dl and/or transfusion of 2 units *Some patients had >1 event Safety population 18 (0.7) 26 (1.1) HR (95% CI) p-value 0.49 (0.31 0.80) p=0.0032

EINSTEIN Extension Treatment for index VTE event 6 or 12 months anticoagulation Continue anticoagulation Equipoise Should anticoagulation be stopped or continue? Stop treatment Routine coagulation monitoring, with dose adjustment and attendant risk of bleeding EINSTEIN Extension The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

30-day observation period EINSTEIN Extension Randomized, double-blind, placebo-controlled, superiority study Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA in EINSTEIN programme ~53% Treatment period of 6 or 12 months Day 1 N=1197 R 20 mg od Placebo Confirmed symptomatic DVT or PE completing 6 or 12 months of VKA ~47% Mean duration of anticoagulant therapy Before study entry: Placebo group: 249 days group: 248 days During study: Placebo group: 190 days group: 190 days The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

Cumulative event rate (%) EINSTEIN Extension: primary efficacy outcome time to first event 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Number needed to treat to prevent 1 primary efficacy outcome: 15 Placebo (N=594) HR=0.18; p<0.001 RRR=82% (N=602) 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of subjects at risk 602 590 583 573 552 503 482 171 138 132 114 92 81 Placebo 594 582 570 555 522 468 444 164 138 133 110 93 85 RRR, relative risk reduction The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

EINSTEIN Extension: primary efficacy outcome and individual components (N=602) Placebo (N=594) n (%) n (%) Symptomatic recurrent VTE* 8 (1.3) # 42 (7.1) Recurrent DVT 5 (0.8) 31 (5.2) Non-fatal PE 2 (0.3) 13 (2.2) Fatal PE 0 (0) 1 (0.2) Unexplained death (where PE cannot be excluded) 1 (0.2) 0 (0) ITT population; *Some patients experienced more than one event; # p<0.001 The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

EINSTEIN Extension: major bleeding (N=598) Placebo (N=590) n (%) n (%) Major bleeding 4 (0.7)* 0 (0) Bleeding contributing to death 0 (0) 0 (0) Bleeding in a critical site 0 (0) 0 (0) Associated with fall in haemoglobin 2 g/dl and/or transfusion of 2 units 4 (0.7) 0 (0) Gastrointestinal bleeding 3 (0.5) 0 (0) Menorrhagia 1 (0.2) 0 (0) Number needed to harm: approximately 139 Safety population; *p=0.11 The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

EINSTEIN Extension: non-major clinically relevant bleeding (N=598) Placebo (N=590) n (%) n (%) Non-major clinically relevant bleeding 32 (5.4)* 7 (1.2) Urogenital/uterus 12 (2.0) 2 (0.3) Nasal 8 (1.3) 1 (0.2) Rectal/anal 6 (1.0) 2 (0.3) Skin 4 (0.7) 2 (0.3) Ear 1 (0.2) 0 (0) Gastrointestinal 1 (0.2) 0 (0) Surgical site 1 (0.2) 0 (0) Safety population; some patients experienced more than one event. *p<0.01 The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510

VTE Therapy current challenges & opportunities כנס האיגוד הישראלי לפרמקולוגיה קלינית 2012 04-May-2012